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Vol.18, No.

1 January 1996

Continuing Education Article

Dyslipoproteinemia of
FOCAL POINT
Chronic Renal Failure:
★ Control of dyslipoproteinemia
may become important in
Its Relevance to
the treatment of renal failure
in dogs. Canine Progressive
KEY FACTS Kidney Disease
■ The dyslipoproteinemia that
results from renal disease may
contribute to the progression of University of Illinois
renal failure. Lisa Kurosky Down, DVM
Donald R. Krawiec, DVM, PhD
■ Reduction of hyperlipidemia
through diet or medication has
reduced renal damage in
experiments with various species.

■ Canine low-density lipoprotein


D isorders of lipid metabolism have been associated with chronic renal
disease in humans and dogs for many years. Most attention has been
focused on the abnormalities found in concert with protein-losing
nephropathy (especially the hypercholesterolemia associated with nephrotic
syndrome). Recent investigations have shown that human patients with chron-
and high-density lipoprotein are
metabolically similar to their ic renal disease without proteinuria have abnormal lipoprotein distributions
human counterparts but are more (dyslipoproteinemia).1–7 Other reviews of lipid abnormalities in association
difficult to separate because their with chronic renal failure have been published.1–3
density ranges overlap, Figure 1. Dyslipoproteinemia occurs regardless of the underlying cause of chronic re-
nal failure, and the severity of dyslipoproteinemia is directly proportional to
■ A precipitation technique for the degree of renal impairment.5 Dyslipoproteinemia probably contributes to
measuring canine lipoprotein has the increased risk of cardiovascular disease among humans with kidney failure.8
recently been validated. Moorhead and coworkers were the first to propose that lipid abnormalities may
directly contribute to the progression of renal disease.9 Subsequently, studies of
humans and animals have been designed to investigate this hypothesis. Cur-
rently, little is known about lipid abnormalities in dogs with nonnephrotic
chronic renal failure.

LIPOPROTEIN CHEMISTRY AND CLASSIFICATION


Lipoproteins are macromolecules composed of various lipids, sterols, and
specific protein components called apolipoproteins (apoproteins). Lipoprotein
particles are typically spherical and are characterized by a surface monolayer of
polar lipids (primarily phospholipids) and apoproteins. The hydrophobic cen-
tral core contains triglycerides and esterified cholesterol. The relative propor-
Small Animal The Compendium January 1996

tion of triglycerides to cholesterol TABLE I


within each lipoprotein particle Density Ranges of Canine and Human Plasma Lipoproteina
varies according to the type of
lipoprotein and may also differ in Density Ranges (g/ml)
Lipoprotein Electrophoretic
disease states and between species. Fractionb Fractionc Canine Human
Lipoproteins can be subdivided
Chylomicrons Origin NEd 0.93
into various classes associated with VLDL Pre-β <1.006 0.93–1.006
some specific metabolic functions. IDL Pre-β NE 1.006–1.019
The major lipoprotein classes are LDL β 1.006–1.087 1.019–1.063
named in relation to their density HDL1 α2 1.025–1.10 NE
(Table I). Lipoprotein classification HDL2 α1 1.070–1.21 1.063–1.125
was initially developed for humans HDL3 α1 NE 1.125–1.210
and has been extended for other a Data from Havel RJ, Kane JP: Introduction: Structure and metabolism of plasma
species.10 The five major lipopro- lipoproteins, in Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic Basis of
tein classes are chylomicrons, very- Inherited Disease. New York, McGraw-Hill, 1989, pp 1129–1138; and Mahley RW,
low-density lipoprotein (VLDL), Weisgraber KH: Canine lipoproteins and atherosclerosis I. Isolation and characterization
intermediate-density lipoprotein of plasma lipoproteins from control dogs. Circ Res 35:713–721, 1974.
b VLDL = very-low-density lipoprotein; IDL = intermediate-density lipoprotein; LDL =
(IDL), low-density lipoprotein
low-density lipoprotein; and HDL = high-density lipoprotein.
(LDL ), and high-density lipopro- c Electrophoretic definition of lipoprotein fractions; see Figure 1.
tein (HDL ).11,12 d NE = no evidence of or not determined.

Lipoprotein Metabolism
Chylomicrons absorbed from the gastrointestinal depends on the concentration, distribution, and func-
tract and VLDL particles formed by the intestine and tion of these important proteins.
liver are composed mainly of triglycerides, which are re-
leased to tissue by the action of lipoprotein lipase en- SPECIES COMPARISON
zymes. Low-density lipoprotein particles formed by the Lipoproteins are fairly similar across species; however,
liver are the major carriers of cholesterol in humans and some differences exist.10 In dogs, for example, HDL
are taken up as needed by tissue through interaction particles carry most of the serum cholesterol (Tables II
with a specific LDL receptor.11–13 High-density lipopro- and III). Also, a cholesterol-laden HDL subclass (HDLc
teins are responsible for transporting cholesterol back or HDL1) is a routine finding in canine lipoprotein
to the liver. Through the action of the enzyme profiles but is not typically seen in healthy individuals
lecithin:cholesterol acyltransferase and cholesterol ester of other species.18–20 The density ranges are slightly dif-
transfer protein, HDL particles can transfer cholesterol ferent for canine lipoproteins than for those of humans
between lipoprotein molecules and return cholesterol (Table I). Figure 1 compares the agarose gel elec-
to the liver for excretion.11–13 trophoresis of human lipoproteins with that of canine
lipoproteins.21 However, no great differences in the
Apoproteins metabolic functions of the lipoprotein classes between
In healthy individuals, the particles within each class these species have been noted.
of lipoprotein have characteristic profiles of apolipopro-
teins or apoproteins on their surfaces. For example, apo DYSLIPOPROTEINEMIA
B-48 is found exclusively on chylomicron particles The dyslipoproteinemia observed in humans with
whereas apo B-100 is primarily associated with LDL.12 nonnephrotic chronic renal disease is characterized by
Apo A-I and apo A-II predominate in HDL parti- changes in the proportion of triglycerides and choles-
cles.12,14 Apoproteins determine the metabolic functions terol within lipoprotein classes. Affected humans exhib-
of the lipoprotein particles by binding with various it elevations in the triglyceride fraction of VLDL, LDL,
lipoprotein receptors as well as through other interac- and HDL molecules.1,5 Blood levels of triglyceride may
tions. For example, apo B-100 and apo E are both li- or may not be elevated coincidentally, depending on
gands for LDL receptors12,13,15,16 whereas apo C inhibits the severity of the disease.7 Total cholesterol is usually
the uptake of particles that contain apo E.17 Apo A-I, moderately increased because of a rise in VLDL choles-
apo A-IV, and apo C-I are activators of lecithin:choles- terol, although HDL cholesterol is decreased.1,5 In addi-
terol acyltransferase13; and apo C-II is an activator of tion, chylomicron remnants and IDL accumulate.22
lipoprotein lipase.12–14 Normal lipoprotein metabolism In these humans, the normal apoprotein patterns of

LIPOPROTEIN CLASSES ■ APOPROTEIN PROFILES ■ METABOLIC FUNCTIONS


The Compendium January 1996 Small Animal

TABLE II
Lipid Distribution in Normal Canine Plasma Lipoproteina
Lipoprotein Triglycerides Cholesterol Cholesteryl Esters c Phospholipids
Fractionb (mg/100 ml) (mg/100 ml) (mg/100 ml) (mg/100 ml)
VLDL 9.0 ± 1.7 2.3 ± 0.5 1.8 ± 0.5 2.5 ± 1.0
LDL 7.6 ± 1.8 5.7 ± 1.9 4.23 ± 0.2 6.4 ± 1.8
HDL1 0.3 ± 0.05 4.6 ± 1.4 3.4 ± 0.2 5.4 ± 1.3
HDL2 2.2 ± 0.3 70.0 ± 12.0 51.5 ± 1.3 124.6 ± 10.3
a From Mahley RW, Weisgraber KH: Canine lipoproteins and atherosclerosis I. Isolation and characterization of plasma lipoproteins

from control dogs. Circ Res 35:713–721, 1974. Reproduced with permission. Results are means ± SE from duplicate determinations
on plasma from four dogs.
b VLDL = very-low-density lipoprotein; LDL = low-density lipoprotein; and HDL = high-density lipoprotein.
c Expressed as cholesterol equivalents.

TABLE III
Normal Canine Plasma Lipid Levelsa
Triglycerides Total Cholesterol Cholesteryl Esters b Phospholipids
(mg/dl) (mg/dl) (mg/dl) (mg/dl)
Mean 36 127 97 302
Range 15–70 60–185 40–150 198–437
a Results are from duplicate determinations on plasma from 25 control dogs. From Mahley RW, Weisgraber KH: Canine lipoproteins

and atherosclerosis I. Isolation and characterization of plasma lipoproteins from control dogs. Circ Res 35:713–721, 1974. Reproduced
with permission.
b Expressed as cholesterol equivalents.

the lipoprotein classes are shifted. Apoprotein changes underlying mechanisms have been proposed. Consider-
include reduction in plasma levels of apo A-I, apo A-II, able evidence points to a reduction in lipoprotein lipase
and apo E and concurrent, marked elevation in apo C- activity in tissue and the liver,4,24 perhaps under the in-
III.5–7 Moderate elevations in apo C-I, apo C-II, and fluence of an inhibitor substance. 25 McCosh and
apo B may also be observed.7 Elevations in apo(a), coworkers reported hypertriglyceridemia and decreased
which is the apoprotein of Lp(a), also occur. Apo(a) is a postheparin lipolytic activity among renal-failure pa-
human apoprotein structurally similar to plasminogen. tients undergoing long-term dialysis.4 Notably, these re-
High plasma levels of its associated lipoprotein, Lp(a), searchers found that the reduction in posthepatic
have been found to be an important risk factor for lipolytic activity was directly proportional to the degree
coronary artery disease.23 of renal failure.4 Murase and coworkers reported that in
The described dyslipoproteinemia of chronic renal vitro activity of lipoprotein lipase was significantly low-
failure can be detected early in the course of disease5,7; er in uremic plasma than in normal plasma.25 Dialysis
the severity of the lipid abnormalities is directly propor- of the uremic sera before incubation with the enzyme
tional to the degree of renal azotemia.5 Attman and did not alter these results.25
Alaupovic7 showed that nondialyzed patients with early A study of dogs points to secondary hyperparathy-
renal failure exhibited characteristic changes in roidism as a potential cause of lipoprotein lipase defi-
apolipoprotein patterns. These apoprotein changes be- ciency.26 This study of dogs with experimentally in-
came more pronounced with increased severity of dis- duced renal failure showed that dogs that had also
ease and were associated with the development of hy- undergone parathyroidectomy have normal serum
pertriglyceridemia and hypercholesterolemia.7 triglycerides and postheparin lipolytic activity when
compared with the dogs that had not undergone
Pathogenesis parathyroidectomy. Excess parathyroid hormone is be-
The pathogenesis of the dyslipoproteinemia of lieved to suppress insulin release, thus resulting in car-
chronic renal failure is not fully understood, but several bohydrate intolerance. Insulin deficiency also causes

LIPOPROTEIN LIPASE ACTIVITY ■ HYPERPARATHYROIDISM


Small Animal The Compendium January 1996

decreased synthesis of lipoprotein lipase.26 In ad-


dition, changes in apoprotein synthesis or
catabolism might alter lipoprotein metabolism.

Mechanisms of Renal Injury


Chronic renal failure is characterized by pro-
gressive decline in kidney function after some
initiating event. Chronic renal disease can con-
tinue to progress even in the absence of the origi-
nal inciting cause, seemingly because of intrinsic
self-perpetuating mechanisms. The histologic re-
sult is often global and focal glomerulosclerosis
and interstitial fibrosis.
Many factors have been considered as contrib-
utory to the development of focal glomeruloscle-
rosis. Altered hemodynamics with increased
glomerular capillary flows and pressures, coagu-
lation abnormalities, altered renal prostaglandin
production, and damage to the epithelial cells of Figure 1—Comparison of human and canine densitometric tracings of
glomeruli may be significant.27 Recently, howev- normal serum lipoprotein distributions after agarose gel electrophore-
er, interest has been focused on the role that ab- sis and lipid staining. (From Bauer JE: Diet-induced alterations of
normal lipid metabolism may play in the pro- lipoprotein metabolism. JAVMA 201:1691–1694, 1992. Modified
gression of renal injury.27–30 with permission.) See Table I for identification of lipoproteins con-
tained in each electrophoretic fraction.
Role of Lipids
Increased levels of circulating VLDL and LDL
may result in increased deposition or entrapment of ease, the incidence of renal disease among patients with
these lipoproteins in the mesangial matrix. The cationic common primary hyperlipidemia is low. Lipids might
lipoprotein molecules ionically bind to glycosaminogly- only perpetuate renal injury once an initiating event
cans in the matrix.27 Increased circulating LDL and occurs; perhaps lipids require additional predisposing
VLDL may also result in increased levels of oxidized factors, such as hypertension, to cause renal injury. One
lipoproteins generated by endothelial cells, macrophages, exception is found in humans with lecithin:cholesterol
and perhaps contractile glomerular mesangial cells.27–29 acyltransferase deficiency, a hereditary condition result-
Any locally generated oxidized LDL would be directly ing in an inability to esterify cholesterol. The character-
toxic to mesangial cells.28 Hyperlipidemia is also associat- istic features of this condition include lipid deposition
ed with alterations in the lipids of endothelial cell mem- in glomeruli and progressive renal failure.31 Probably
branes; these alterations may result in enhanced mono- the first recognized association between lipid abnormal-
cyte adhesion and therefore increased influx of ities and renal failure was in diabetic nephropathy.32
monocytes into the mesangial matrix.28 The rate of decline in renal function of humans with
Macrophages can take up modified LDL or VLDL diabetes has been shown to correlate, in part, with
by endocytosis, thus becoming foam cells.27–29 Glomer- serum cholesterol levels.28
ular foam cells produce increased amounts of vasocon-
strictor eicosanoids (e.g., thromboxane A2), thus alter- Animal Studies
ing glomerular eicosanoid balance.29 Altered glomerular Several animal models have shown a relationship be-
macrophages or foam cells may also produce toxic oxy- tween total serum cholesterol and renal function. For
gen radicals and release cytokines.29 Each of these con- example, guinea pigs fed a 1% cholesterol diet had a
sequences results in cell proliferation and matrix over- significantly increased incidence of focal glomeruloscle-
production in the mesangium, thus leading to rosis when compared with animals fed the base diet.33
glomerulosclerosis. Results were similar for New Zealand white rabbits fed
a high-cholesterol diet.34 In both cases, focal glomeru-
RENAL DISEASE AND HYPERLIPIDEMIA losclerosis was preceded by glomerular enlargement,
In Humans mesangial expansion, and hypercellularity. Diamond
Although hyperlipidemia is correlated with renal dis- and Karnovsky 35 showed that the degree of focal

ALTERED HEMODYNAMICS ■ FOAM CELLS ■ DIETARY CHOLESTEROL


Small Animal The Compendium January 1996

glomerulosclerosis that developed in rats after nephrosis We recently presented the


was induced with puromycin aminonucleoside was sig- first evidence that dogs with Dyslipoproteinemia
nificantly greater in those fed a 4% cholesterol diet. nonnephrotic renal failure in Humans
Rats eating the high-cholesterol diet exhibited a greater may have lipid abnormalities
fasting serum cholesterol value and an increased per- similar to those characterized ■ Affected patients
centage of glomeruli with focal glomerulosclerosis, in the dyslipoproteinemia of exhibit elevations in
mesangial cell proliferation, and mesangial foam cells.35 human renal failure.38 Lipid the triglyceride
A genetic mutant of the Zucker rat exhibits hyper- changes observed included fraction of VLDL, LDL,
cholesterolemia, hypertriglyceridemia, obesity, and renal hypercholesterolemia, a shift and HDL molecules.
failure and has been exten- in the distribution of choles-
■ Total cholesterol is
Dyslipoproteinemia sively studied.36,37 Expansion terol from the HDL to the
of the mesangial matrix of LDL fraction, and elevations usually moderately
in Dogs increased because of
glomeruli, albuminuria, and in triglyceride content of the
■ Whether characteristic progressive focal glomeru- LDL and HDL fractions a rise in VLDL
dyslipoproteinemia losclerosis occur in rats with with a concurrent reduction cholesterol, although
this mutation. Micropunc- in VLDL triglycerides. HDL cholesterol is
occurs in conjunction
ture studies of affected rats Analysis of classes of canine
with nonnephrotic decreased.
did not reveal altered hemo- lipoproteins is technically dif-
renal failure is dynamics within the glomer- ficult. The overlapping densi- ■ The normal apoprotein
unknown. ulus compared with that of ty ranges of canine lipopro- patterns of the
■ Analysis of the nonobese siblings that lacked teins (Table I), especially with lipoprotein classes
lipoprotein classes the mutation. 37 Medical regard to HDL 1 and LDL, are shifted.
management of the affected makes density-gradient sepa- ■ Dyslipoproteinemia
is technically
rats’ hypercholesterolemia, ration by ultracentrifuge in-
demanding. can be detected early
however, significantly reduced complete. In addition, poly-
■ The density ranges renal damage.30 anion precipitation tests in the course of
of the lipoproteins Keane and coworkers re- heavily used in analysis of hu- chronic renal failure,
overlap, thus making ported similar findings using man lipoproteins either do and the severity of the
density-gradient a rat remnant kidney (i.e., not fully separate the canine lipid abnormalities is
rats from which most of the HDL and LDL fractions39 or directly proportional
separation by
kidney mass has been ex- have not been validated for
ultracentrifuge to the degree of renal
cised) as a model for progres- canine lipoproteins. However,
incomplete. sive focal glomerulosclero- quantitative techniques are azotemia.
■ Polyanion sis.30 These researchers found available, including starch gel
precipitation tests that treatment of these rats electrophoresis.18 Also, a precipitation technique for ca-
heavily used in with clofibric acid or mevin- nine lipoproteins was recently validated by Barrie and
olin to reduce the hyperlipi- coworkers.40
analysis of human
demia reduced albuminuria
lipoproteins either do and the incidence of focal SUMMARY
not fully separate the glomerulosclerosis.30 Thus, a The dyslipoproteinemia of human nonnephrotic
high-density and substantial body of evidence chronic renal failure is characterized by overall hyper-
low-density canine supports the hypothesis that triglyceridemia and hypercholesterolemia. Characteris-
lipoprotein fractions hyperlipidemia in association tic changes in the various apolipoprotein concentra-
with chronic renal failure tions and distributions are also noted. These changes
or have not been
plays a significant role in the are detectable early in the course of disease, and the
validated for canine development of progressive severity of changes correlates with the degree of under-
lipoproteins. kidney disease. lying renal failure. The impact of dyslipoproteinemia
■ Starch gel on the patient is still not entirely known.
electrophoresis can Studies of Dogs The incidence of cardiovascular complications
be used to quantitate Less is known about dys- among humans with renal failure is well established.8
lipoproteinemia occurring in Development of the dyslipoproteinemia of chronic re-
canine lipoproteins.
dogs in conjunction with nal failure, especially the generation of the Lp(a) pro-
nonnephrotic renal failure. tein, may be highly correlated with the occurrence of

CHOLESTEROL-LOWERING DRUGS ■ CANINE LIPOPROTEIN FRACTIONS


Small Animal The Compendium January 1996

these complications. As outlined above, a growing body Valle D (eds): The Metabolic Basis of Inherited Disease. New
of evidence indicates that lipid abnormalities may also York, McGraw-Hill, 1989, pp 1129–1138.
12. Gotto AM, Pownall HJ, Havel RJ: Introduction of the plas-
be important in the progression of the renal disease. ma lipoproteins. Meth Enzymol 128:3–41, 1986.
Discovery of the role that lipids play in promoting re- 13. Scanu AM: Physiopathology of plasma lipoprotein
nal disease is especially important in light of the avail- metabolism. Kidney Int 39(suppl 31):S-3–S-7, 1991.
ability of drugs for the manipulation of lipoproteins 14. Nilsson-Ehle P, Garfinkel AS, Schotz MC: Lipolytic en-
and cholesterol. Continued research in this area of zymes and plasma lipoprotein metabolism. Annu Rev
Biochem 49:667–693, 1980.
nephrology may lead to better management and con- 15. Sherrill BC, Innerarity TL, Mahley RW: Rapid hepatic
trol of chronic renal disease and has the ultimate goal clearance of the canine lipoproteins containing only the E
of altering the progressive nature of renal disease. apoprotein by a high affinity receptor. J Biol Chem 255(5):
Dogs are certainly less susceptible to atherosclerosis 1804–1807, 1980.
than humans are, so cardiovascular complications are 16. Angelin B, Raviola CA, Innerarity TL, Mahley RW: Regula-
tion of hepatic lipoprotein receptors in the dog. Rapid regu-
less of a concern. However, the potential involvement lation of apolipoprotein B, E receptors, but not of
of dyslipoproteinemia in the progression of canine apolipoprotein E receptors, by intestinal lipoproteins and
chronic renal failure is an intriguing and as yet unex- bile acids. J Clin Invest 71:816–831, 1983.
plored area of canine nephrology. 17. Sehayek E, Eisenberg S: Mechanisms of inhibition by
apolipoprotein C of apolipoprotein E dependent cellular
metabolism of human triglyceride-rich lipoproteins through
the low density lipoprotein receptor pathway. J Biol Chem
About the Authors 266(27):18259–18267, 1991.
Drs. Down and Krawiec are affiliated with the Department 18. Mahley RW, Weisgraber KH: Canine lipoproteins and
of Veterinary Clinical Medicine of the College of Veteri- atherosclerosis. I. Isolation and characterization of plasma
lipoproteins from control dogs. Circ Res 35:713–721, 1974.
nary Medicine, University of Illinois, Urbana, Illinois. Dr. 19. Mahley RW, Weisgraber KH, Innerarity TL: Canine
Krawiec is a Diplomate of the American College of Veteri- lipoproteins and atherosclerosis. II. Characterization of the
nary Internal Medicine. plasma lipoproteins associated with atherogenic and
nonatherogenic hyperlipidemia. Circ Res 35:722–733, 1974.
20. Mahley RW, Weisgraber KH: Canine plasma lipoproteins:
Characterization of lipoproteins from control and choles-
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